The Lung Cancer Biology Section has studied the effect of prolonged exposure of paclitaxel to lung cancer and the rate of developing second cancers in a large North American cohort of patients surviving small cell lung cancer. Twenty-eight lung cancer cell lines were studied with increasing durations of exposure to paclitaxel. The median paclitaxel concentration required to inhibit 50% of the growth of 14 non-small cell lung cancer (NSCLC) cell lines measured by MTT assay decreased more than 1000-fold when the exposure duration increased from 3 to 120 hours. The median paclitaxel concentration required to inhibit 50% of the cell growth of SCLC cell lines decreased 10-fold when the exposure duration increased from 3 to 120 hours. Based on this in vitro, we performed a phase I trial of a 96 hour infusion of paclitaxel followed by cisplatin. Fifty patients with previously untreated lung cancer (42 with NSCLC and 8 with SCLC) were treated with increasing doses of paclitaxel administered as a 96 hour infusion followed by increasing doses of cisplatin. The recommended phase II dose was 120 mg/m of paclitaxel and 80 mg per meter squared of cisplatin. The dose limiting toxicity was hematologic. The 42 patients with NSCLC had a response rate of 55%, a median survival of 10 months, and 41% were alive at one year after starting treatment. The recommended phase II dose is now being used in a phase II trial for patients with stage IV and IIIb (with pleural effusion) NSCLC and in a neoadjuvant trial combined with 6000 cGy of chest radiation for patients with stage IIIa and IIIb. A cooperative North American working group from 10 institutions identified 611 patients surviving two or more years after treatment for small cell lung cancer who developed 87 second cancers, a 3.5-fold increased relative risk. This was principally caused by an 11-fold increase in the risk of lung cancer. The cumulative risk at 12 years for these patients was 30%. Chest irradiation and continuing cigarette smoking contributed to the increased risk. A chemoprevention trial for this population has been organized.